Publications by authors named "Mark R Green"

64 Publications

First-Line Treatment with Bevacizumab and Platinum Doublet Combination in Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Cohort Study in US Oncology Community Practices.

Drugs Real World Outcomes 2016 Sep;3(3):333-343

Genentech, Inc., 1 DNA Way, San Francisco, CA, 94080, USA.

Background: Real-world evidence is lacking on the impact of bevacizumab added to carboplatin/paclitaxel (Bev + CP) therapy versus CP alone for patients with non-squamous non-small cell lung cancer (NS-NSCLC), particularly in those excluded from clinical trials.

Methods: This is a retrospective electronic medical record analysis of patients who received first-line therapy with Bev + CP or CP between 1 October 2006 and 30 June 2013. We identified four subsets: elderly patients (≥65 years), patients with brain/central nervous system (CNS) metastases, patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and patients receiving anticoagulation. We used descriptive statistics to describe patient characteristics and treatment patterns and evaluated progression-free survival (PFS) and overall survival (OS) using survival analyses.

Results: The study included 431 patients (Bev + CP: 231; CP: 200). The Bev + CP cohort was more likely to receive four or more cycles of induction therapy (72 vs. 50 %) and was more likely to receive maintenance therapy (45 vs. 21 %) than patients receiving CP. In the overall population, median PFS and OS were significantly longer in the Bev + CP cohort than in the CP cohort: 6.7 vs. 5.1 months (hazard ratio [HR] 0.74; 95 % confidence interval [CI] 0.59-0.92; p = 0.008) and 11.9 vs. 9.0 months (HR 0.57; 95 % CI 0.44-0.73; p < 0.001), respectively. Treatment with Bev + CP in patients aged ≥65 years and in those with brain/CNS metastases was also associated with a significant risk reduction in PFS (35 and 51 %, respectively; p < 0.05 for both) and OS (46 and 62 %, respectively; p < 0.05 for both) compared with CP alone.

Conclusion: Bev + CP is associated with a significant improvement in PFS and OS in patients with NS-NSCLC and in subsets with brain/CNS metastases and those aged ≥65 years.
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http://dx.doi.org/10.1007/s40801-016-0090-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042946PMC
September 2016

Surgical Resection Preferences and Perceptions among Medical Oncologists Treating Liver Metastases from Colorectal Cancer.

Ann Surg Oncol 2016 Feb 11;23(2):375-81. Epub 2015 Nov 11.

Xcenda LLC, AmerisourceBergen Consulting Services, Palm Harbor, FL, USA.

Background: Liver resection is a key therapeutic strategy to improve survival in patients with colorectal cancer liver metastases. Underutilization may negatively affect outcomes. Using a Web-based survey and standardized imaging scenarios, this study assessed medical oncologists' (MOs) perceptions of resectability, preferences for chemotherapy sequencing, and referral for surgical consultation in a static patient profile of good performance status and no extrahepatic spread but varying bulk and distribution of disease.

Methods: A total of 190 US-based MOs were surveyed. A single patient profile was created and combined with 10 different sets of liver computed tomographic images displaying a broad spectrum of metastases. Assessments of resectability and ranking were compared with the results obtained from an expert panel of 3 hepatic surgeons.

Results: The expert hepatic surgeons designated 8 scans resectable, 1 borderline resectable/convertible, and 1 unresectable. In the 8 resectable cases, 34.4 % of MOS perceived the case to be initially resectable, 41.7 % potentially resectable after chemotherapy response, and 23.9 % unresectable. Increasing number of lesions, larger tumor diameter, and bilateral disease were associated with lower resectability perception (P < 0.01). Among those cases considered resectable by MOs, they preferred initial resection (54.2 %) over neoadjuvant chemotherapy (38.4 %). Initial referral for surgical consultation was generally favored only for cases considered initially resectable by MOs.

Conclusions: This study confirms both potential discrepancies between MOs' and hepatic surgeons' perception of resectability and underutilization of early surgical consultation for patients with potentially resectable colorectal cancer liver metastases and underscores the importance of an evaluation that includes an experienced hepatic surgeon.
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http://dx.doi.org/10.1245/s10434-015-4925-1DOI Listing
February 2016

A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere.

Cancer Chemother Pharmacol 2014 Apr 23;73(4):839-45. Epub 2014 Feb 23.

Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Ave St 3300, Miami, FL, 33136, USA.

Purpose: Docetaxel and capecitabine combination is synergistic in preclinical models. We investigated the efficacy and toxicity of this combination as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma (mPC), pretreated with gemcitabine-based chemotherapy.

Methods: Eligible patients were treated with capecitabine 800 mg/m(2) orally PO bid on days 1-14 in combination with intravenous docetaxel 30 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall response rate. Using a three-stage sequential design, two interim analyses for early stopping due to lack of efficacy were planned and conducted after 13 and 26 patients were accrued. Secondary end points included time to treatment failure, progression-free survival (PFS), overall survival (OS) and 50 % drop in CA19-9 levels.

Results: Forty-three patients were evaluable for toxicity and 42 evaluable for response, at a median age of 64 years. The majority of patients (74 %) had ECOG PS 0-1. Six patients (14 %) achieved a partial tumor response, and stable disease for ≥2 cycles was observed in 59 % of patients (n = 25). Thirty-five percent (n = 11/31) of patients had a ≥50 % decrease in CA19-9 levels. The median PFS was 3.7 months (95 % CI 2.1-4.3 months), and the median OS was 5.3 months (95 % CI 4.3-8.6 months). Treatment was generally well tolerated. Grade 3 toxicity and grade 4 toxicity were seen in 45 and 5 % of patients, respectively. One patient had a potential treatment-related mortality.

Conclusions: The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.
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http://dx.doi.org/10.1007/s00280-014-2414-zDOI Listing
April 2014

Cost effectiveness of first-line pemetrexed plus platinum compared with other regimens in the treatment of patients with nonsquamous non-small cell lung cancer in the US outpatient setting.

Lung Cancer 2013 Oct 7;82(1):121-7. Epub 2013 Aug 7.

Xcenda, 4114 Woodlands Parkway, Palm Harbor, FL 34685, USA.

This retrospective observational study evaluated cost effectiveness of first-line treatment of advanced nonsquamous non-small cell lung cancer (NSCLC) with pemetrexed/platinum (Pem/Plat) relative to paclitaxel/carboplatin (Pac/Carbo) and paclitaxel/carboplatin/bevacizumab (Pac/Carbo/Bev). Patients initiating first-line treatment from 2006 to 2009 were identified in electronic medical records of 20 US oncology practices. Pem/Plat patients were matched 1:1 on important characteristics with Pac/Carbo and Pac/Carbo/Bev patients and followed for 1 year to assess progression, survival, and costs. Bootstrapping was used to calculate the probability of falling within quadrants of the incremental cost-effectiveness plane. Kaplan-Meier analysis and Cox proportional hazards regression modeling were also performed. Three hundred Pem/Plat patients (mean age, 67.6 years; male, 56.0%; PS 0/1, 71.0%) were matched with 300 patients in the other cohorts. Median PFS was 134 days (Pem/Plat) versus 106 days (Pac/Carbo) (hazard ratio [HR]: 0.67, P < 0.001) and 126 days (Pac/Carbo/Bev) (HR: 0.68, P < 0.001). Median OS was 298 days (Pem/Plat) versus 218 days (Pac/Carbo) (HR: 0.88, P = 0.08) and 271 days (Pac/Carbo/Bev) (HR: 0.93, P = 0.31). Pem/Plat therapy costs were higher versus Pac/Carbo ($21,841 higher PFS; $19,137 higher OS; P ≤ 0.05) and lower versus Pac/Carbo/Bev ($15,160 lower PFS; $19,946 lower OS; P ≤ 0.05). Pem/Plat had a greater probability of higher costs/higher effectiveness versus Pac/Carbo (PFS, 90.1%; OS, 96.3%) and lower costs/higher effectiveness versus Pac/Carbo/Bev (PFS, 69.5%; OS, 85.0%). Pem/Plat had higher cost and effectiveness than Pac/Carbo; depending on a payer's or society's willingness to pay, Pem/Plat may be considered cost effective compared with Pac/Carbo. Pem/Plat yielded greater effectiveness with lower costs than Pac/Carbo/Bev.
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http://dx.doi.org/10.1016/j.lungcan.2013.07.021DOI Listing
October 2013

Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206.

J Thorac Oncol 2013 Jan;8(1):102-8

Medical Service, Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.

Introduction: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer.

Methods: Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m and irinotecan 65 mg/m intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival.

Results: Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%-81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%-94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4-14.7) and 18.1 months (15.8-22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities.

Conclusions: This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development.
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http://dx.doi.org/10.1097/JTO.0b013e31827628e1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524334PMC
January 2013

Physician preferences for management of patients with stage IIIA NSCLC: impact of bulk of nodal disease on therapy selection.

J Thorac Oncol 2012 Feb;7(2):365-9

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Introduction: Stage IIIA non-small cell lung cancer (NSCLC) constitutes a heterogeneous group of patients with predominant ipsilateral mediastinal (N2) disease. The spectrum of lymph node presentation has lead to a host of trials involving various therapeutic combinations, and optimal management has been unclear.

Methods: In 2007 and 2008, 10 live research events surveyed the practice preferences of American medical oncologists using two hypothetical scenarios. The first scenario was of a stage IIIA NSCLC in the right upper lobe with a single enlarged (>1 cm) 4R lymph node found to be malignant by mediastinoscopy. The second was of a bulky stage IIIA NSCLC with multistation N2 pathologically positive nodes.

Results: In the first scenario, 373 (92%) of the oncologists incorporated surgery into their treatment plan. Only 34 (8%) offered chemoradiotherapy alone. Neoadjuvant chemotherapy, followed by surgery and then additional chemoradiotherapy (32%), was the most commonly offered treatment strategy. In the second scenario, 209 (52%) medical oncologists chose definitive chemoradiation. A total of 193 (48%) included surgery as part of the treatment plan.

Conclusions: The current standard of care for IIIA N2 NSCLC recognized before treatment is concurrent chemoradiotherapy. This study demonstrated that a significant proportion of oncologists treating locally advanced lung cancer include surgery as part of the treatment plan more so in single versus multinodal station disease. Since node positive locally advanced disease is such a common presentation for patients with lung cancer, well-designed clinical trials are needed to define the most advantageous treatment strategy for individual subsets of patients with stage IIIA disease.
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http://dx.doi.org/10.1097/JTO.0b013e31823a385fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527069PMC
February 2012

Cisplatin, irinotecan, and bevacizumab for untreated extensive-stage small-cell lung cancer: CALGB 30306, a phase II study.

J Clin Oncol 2011 Nov 3;29(33):4436-41. Epub 2011 Oct 3.

Duke University Medical Center, Durham, NC 27710, USA.

Purpose: The efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC).

Patients And Methods: Patients with ES-SCLC received cisplatin 30 mg/m(2) and irinotecan 65 mg/m(2) on days 1 and 8 plus bevacizumab 15 mg/kg on day 1 every 21 days for six cycles on this phase II study. The primary end point was to differentiate between 50% and 65% 12-month survival rates.

Results: Seventy-two patients were enrolled between March 2005 and April 2006; four patients canceled, and four were ineligible. Grade 3 or 4 toxicities included neutropenia (25%), all electrolyte (23%), diarrhea (16%), thrombocytopenia (10%), fatigue (10%), nausea (10%), hypertension (9%), anemia (9%), infection (7%), vascular access thrombosis (2%), stroke (2%), and bowel perforation (1%). Three deaths (5%) occurred on therapy as a result of pneumonitis (n = 1), stroke (n =1), and heart failure (n = 1). Complete response, partial response, and stable disease occurred in three (5%), 45 (70%), and 11 patients (17%), respectively. Progressive disease occurred in one patient (2%). Overall response rate was 75%. Median progression-free survival (PFS) was 7.0 months (95% CI, 6.4 to 8.4 months). Median overall survival (OS) was 11.6 months (95% CI, 10.5 to 15.1 months). Hypertension ≥ grade 1 was associated with improved OS after adjusting for performance status (PS) and age (hazard ratio [HR], 0.55; 95% CI, 0.31 to 0.97; P = .04). Lower vascular endothelial growth factor levels correlated with worse PFS after adjusting for age and PS (HR, 0.90; 95% CI, 0.83 to 0.99; P = .03).

Conclusion: PFS and OS times were higher compared with US trials in ES-SCLC with the same chemotherapy. However, the primary end point of the trial was not met. Hypertension was associated with improved survival after adjusting for age and PS.
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http://dx.doi.org/10.1200/JCO.2011.35.6923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221525PMC
November 2011

Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial.

J Thorac Oncol 2010 Sep;5(9):1382-90

Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Introduction: This study evaluated the addition of gefitinib to sequential or concurrent chemoradiotherapy (CRT) in unresectable stage III non-small cell lung cancer.

Methods: Between May 2002 and April 2005, 63 patients were entered before the study closing early. All received two cycles paclitaxel 200 mg/m and carboplatin area under the curve 6 intravenous plus gefitinib 250 mg daily. Poor risk stratum 1 (> or =5% weight loss and/or performance status 2) received radiotherapy 200 cGy for 33 fractions (6600 cGy) and gefitinib 250 mg daily. Good-risk stratum 2 (performance status: 0-1 weight loss and <5%) received the same RT with gefitinib 250 mg daily and weekly paclitaxel 50 mg/m plus carboplatin AUC 2. Consolidation gefitinib until progression was started after all toxicities were grade < or =2.

Results: Acute high-grade infield toxicities were not clearly increased compared with historical CRT data. Poor-risk (N = 21) median progression-free survival was 13.4 months (95% confidence interval [CI]: 6.4-25.2) and median overall survival 19.0 months (95% CI: 9.9-28.4). Good-risk (N = 39) median progression-free survival was 9.2 months (95% CI: 6.7-12.2), and median overall survival was 13 months (95% CI: 8.5-17.2). Thirteen of 45 tumors analyzed had activating epidermal growth factor receptor (EGFR) mutations, and 2 of 13 also had T790M mutations. Seven tumors of 45 had KRAS mutations. There was no apparent survival difference with EGFR-activating mutations versus wild type or KRAS mutation versus wild type.

Conclusions: Survival of poor-risk patients with wild type or mutated EGFR receiving sequential CRT with gefitinib was promising. Survival for good-risk patients receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations.
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http://dx.doi.org/10.1097/JTO.0b013e3181eba657DOI Listing
September 2010

Prognostic significance of mucin and p53 expression in stage IB non-small cell lung cancer: a laboratory companion study to CALGB 9633.

J Thorac Oncol 2010 Jun;5(6):810-7

Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.

Introduction: Cancer and Leukemia Group B 9633 was a phase III trial that randomized patients with stage IB non-small cell lung cancer to observation or four cycles of carboplatin and paclitaxel. A statistically significant effect in favor of adjuvant chemotherapy was seen for disease-free survival (DFS) and overall survival (OS) in the subgroup of patients with tumors > or =4 cm. A laboratory companion study was conducted to see whether molecular and clinical factors could provide additional prognostic information.

Methods: Formalin-fixed, paraffin-embedded blocks were obtained for 250 of the 344 patients enrolled. Immunohistochemical staining for bcl-2, p53, blood group antigen A, and mucin was correlated with DFS and OS.

Results: The prevalence of the markers was bcl-2, 17%; p53, 47%; blood group antigen A, 25%; and mucin, 45%. Univariate analysis for DFS showed a statistically significant effect for the presence of mucin (p = 0.0005) and p53 (p = 0.05) and for OS showed a significant effect for mucin (p = 0.0005). In the multivariate Cox model, there was a statistically significant association between shorter DFS and presence of mucin (p = 0.002; hazard ratio [HR] 2.05) and p53 (p = 0.003; HR 1.95) and between shorter OS and presence of mucin (p = 0.004; HR 2.03) and p53 (p = 0.0005; HR 2.30). Of the clinical factors, male gender and larger tumor volume were also significant adverse prognostic factors (p 0.05).

Conclusions: A statistically significant association between shorter DFS and OS was seen for the patients with p53 protein expression, mucin expression, male gender, and larger tumors in this cohort of patients with stage IB non-small cell lung cancer treated on Cancer and Leukemia Group B 9633.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505667PMC
http://dx.doi.org/10.1097/jto.0b013e3181d89f95DOI Listing
June 2010

Phase I study of accelerated conformal radiotherapy for stage I non-small-cell lung cancer in patients with pulmonary dysfunction: CALGB 39904.

J Clin Oncol 2010 Jan 23;28(2):202-6. Epub 2009 Nov 23.

Department of Radiation Oncology, State University of New York Upstate Medical University, 750 E Adams St, Syracuse NY 13210, USA.

Purpose: The optimal treatment for medically inoperable stage I non-small-cell lung cancer (NSCLC) has not been defined.

Patients And Methods: Cancer and Leukemia Group B trial 39904 prospectively assessed accelerated, once-daily, three-dimensional radiotherapy for early-stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 or T2N0 NSCLC (< 4 cm) and pulmonary dysfunction. The nominal total radiotherapy dose remained at 70 Gy, while the number of daily fractions in each successive cohort was reduced.

Results: Thirty-nine eligible patients were accrued (eight patients each on cohorts 1 to 4 and seven patients on cohort 5) between January 2001 and July 2005. One grade 3 nonhematologic toxicity was observed in both cohort 3 (dyspnea) and cohort 4 (pain). The major response rate was 77%. After a median follow-up time of 53 months, the actuarial median survival time of all eligible patients was 38.5 months. Local relapse was observed in three patients.

Conclusion: Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiation therapy and limited resection, with less apparent severe toxicity. Further investigation of this approach is warranted.
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http://dx.doi.org/10.1200/JCO.2009.25.0753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815709PMC
January 2010

Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer.

J Thorac Oncol 2009 Sep;4(9):1117-25

University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7305, USA.

Background: In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group.

Patients And Methods: A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb.

Results: Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or or=2 versus patients with or=2 factors (HR = 0.86, 95% CI, 0.63-1.17; p = 0.34) or
Conclusions: There is no evidence that induction chemotherapy is beneficial in either prognostic group.
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http://dx.doi.org/10.1097/JTO.0b013e3181b27b33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778485PMC
September 2009

Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.

Lancet 2009 Aug 24;374(9687):379-86. Epub 2009 Jul 24.

Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153-5589, USA.

Background: Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection.

Methods: Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550.

Findings: 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy.

Interpretation: Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer.

Funding: National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.
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http://dx.doi.org/10.1016/S0140-6736(09)60737-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407808PMC
August 2009

Impact of the ASCO 2007 presentation of HOG Lun 01-24/USO-023 on the prescribing plans of American medical oncologists for patients with stage IIIB non-small cell lung cancer.

J Thorac Oncol 2009 Aug;4(8):983-7

NMCR Analytics, Atlanta, Georgia 30342, USA.

Introduction: Nonoperative treatment of stage III non-small cell lung cancer has evolved over the past 30 years. The current approach in the Unites States most often includes concurrent chemoradiotherapy.

Methods: We have used live, case-based research events to document prescribing plans among American medical oncologists for first-line therapy in patients with N3 stage IIIB non-small cell lung cancer. Changes in prescribing plans documented before and after the 2007 American Society of Clinical Oncology (ASCO) presentation of a Hoosier Oncology Group trial testing the role of consolidation docetaxel chemotherapy in this setting are presented.

Results: Data from 2007 show a post-ASCO shift away from plans for docetaxel consolidation, increased use of concurrent chemoradiotherapy alone, and stable to increased plans for concurrent chemoradiation followed by additional cycles of the chemotherapy used during concurrent management (20%). Preliminary data from 2008 confirm the durability of these changes.

Conclusions: The findings of the Hoosier Oncology Group trial support a transition away from docetaxel consolidation. A trend in this direction among American medical oncologists is clear from our data. However, nearly 20% of oncologists studied in 2008 still plan to use docetaxel consolidation. Furthermore, a majority of those studied after ASCO 2007 continue to report plans to use more than two cycles of chemotherapy as part of their preferred treatment recommendation despite no level I evidence to support this approach.
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http://dx.doi.org/10.1097/JTO.0b013e3181adeefbDOI Listing
August 2009

A phase II study of carboplatin, etoposide, and exisulind in patients with extensive small cell lung cancer: CALGB 30104.

J Thorac Oncol 2009 Feb;4(2):220-6

Washington University School of Medicine and Alvin J Siteman Cancer Center, St Louis, MO 63110, USA.

Purpose: To assess the efficacy and toxicity of carboplatin, etoposide, and exisulind as initial therapy for extensive stage small cell lung cancer.

Patients And Methods: The Cancer and Leukemia Group B conducted a phase II study of carboplatin (area under the curve 6) day 1 and etoposide 80 mg/m(2) days 1-3 administered intravenously every 21 days with exisulind 250 mg orally twice daily in 44 evaluable patients with previously untreated extensive stage small cell lung cancer. The hypothesis was the addition of a novel cytostatic agent to standard therapy may increase survival time. The primary end point of the study was to evaluate overall survival. The secondary end points were to characterize response rates and toxicity.

Results: The majority of the patients were male (64%), Caucasian (95%), and had performance status 0 or 1 (77%). The median age was 61 (range 44-82) years. The percentage of patients alive at 1 year was 36.4% (95% [confidence interval] CI: 24.6-53.8%). The median overall survival was 10.6 months (95% CI: 9.1-14.7). The best overall response rate was 77% (95% CI: 62-89%) with 16% of the patients achieving complete response. The most frequent grade 3 or grade 4 hematological toxicities were neutropenia (64%), thrombocytopenia (36%), and febrile neutropenia (16%). The most common grade 3 or grade 4 nonhematological toxicities were gastrointestinal (30%) and electrolyte changes (23%).

Conclusions: The addition of exisulind to a standard regimen of carboplatin and etoposide did not improve outcomes compared with historic controls treated with chemotherapy alone. Further evaluation of this regimen in small cell lung cancer is not warranted.
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http://dx.doi.org/10.1097/JTO.0b013e3181951eb0DOI Listing
February 2009

Phase II trial of paclitaxel and cisplatin in patients with extensive stage small cell lung cancer: Cancer and Leukemia Group B Trial 9430.

J Thorac Oncol 2008 Nov;3(11):1301-7

Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7305, USA.

Background: Cancer and Leukemia Group B trial 9430 was a randomized phase II trial which investigated the safety and activity of four novel doublets in untreated extensive stage small cell lung cancer. The results of the paclitaxel and cisplatin arm have not been reported.

Patients And Methods: Patients received paclitaxel 230 mg/m followed by cisplatin 75 mg/m on day 1 every 21 days. All patients received granulocyte colony stimulating factor 5 microg/kg/d beginning on day 3 of each cycle.

Results: The patient characteristics of the 34 patients assigned to this treatment arm were: median age 61.5 years (range 41-82), male (76%), performance status 0 (41%), 1 (32%), and 2 (26%). An objective response was observed in 23 patients (68%; 95% confidence interval (CI): 49-83%); 2 complete responses (6%) and 21 partial responses (62%). Median progression-free survival time was 5.6 months (95% CI: 4.8-7.1 month), and median overall survival time was 7.7 months (95% CI: 7.2-12.6 months). The 1-year survival rate observed was 29% (95% CI: 15-45%). Grade 3/4 neutropenia and thrombocytopenia was observed in 5 (15%) and 4 (12%) patients, respectively. Two patients developed febrile neutropenia including one patient who died of neutropenic sepsis. Grade 3/4 nonhematologic observed were: sensory neuropathy in eight patients (24%); and hyperglycemia, malaise and nausea were all observed in four patients (12%).

Conclusions: Cancer and Leukemia Group B will not pursue further investigation of paclitaxel and cisplatin due to the modest activity and the toxicity observed on this trial.
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http://dx.doi.org/10.1097/JTO.0b013e318187494aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696476PMC
November 2008

Tomorrow's cancer treatments today: the first 50 years of the Cancer and Leukemia Group B.

Semin Oncol 2008 Oct;35(5):470-83

Medical University of South Carolina, Charleston, SC, USA.

Members of the Cancer and Leukemia Group B (CALGB) have been striving to improve cancer therapies for more than 50 years. The organization began in the mid 1950s as a multi-institutional collaboration between investigators at the National Cancer Institute, Roswell Park Memorial Institute, and the Children's Hospital in Buffalo New York. In 1956 the group was officially designated as the Acute Leukemia Group B (ALGB) and for most of its first decade focused largely on leukemia research. Reflecting an expansion of its research portfolio during the 1960s and 70s, the name was changed in 1976 to Cancer and Leukemia Group B. Currently, the organization has hundreds of members, including nurses, clinical research associates, statisticians, physicians, translational scientists, and an administrative staff from a nationwide network of academic and community based organizations and medical practices. Disease areas within the scope of CALGB research include hematologic malignancies, as well as breast, gastrointestinal, genitourinary, and respiratory cancers. Modality expertise includes quality of life, medical oncology, surgery, radiation oncology, pathology, imaging, oncology nursing, health outcomes, geriatrics, biostatistics, data management, and an extensive array of correlative sciences. Some of the major accomplishments of CALGB investigators and the patients participating in CALGB research as critical and committed partners will be reviewed here.
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http://dx.doi.org/10.1053/j.seminoncol.2008.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886682PMC
October 2008

Phase II randomized study of dose-dense docetaxel and cisplatin every 2 weeks with pegfilgrastim and darbepoetin alfa with and without the chemoprotector BNP7787 in patients with advanced non-small cell lung cancer (CALGB 30303).

J Thorac Oncol 2008 Oct;3(10):1159-65

Wake Forest University, Winston-Salem, North Carolina, USA.

Introduction: We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787.

Patients And Methods: Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and
Results: Of 160 patients enrolled, 5 never started therapy and 4 were ineligible. Neurotoxicity grade >/=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B].

Conclusions: This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.
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http://dx.doi.org/10.1097/JTO.0b013e318186fb0dDOI Listing
October 2008

Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups.

J Clin Oncol 2008 Nov 22;26(31):5043-51. Epub 2008 Sep 22.

Tufts Medical Center, Division of Medical Oncology, Tufts-NEMC, Boston, MA 02111, USA.

Purpose: Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC.

Patients And Methods: Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival.

Results: Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043).

Conclusion: Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.
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http://dx.doi.org/10.1200/JCO.2008.16.4855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652093PMC
November 2008

Lessons from a time capsule: evolution, not revolution, in therapy for advanced non-small-cell lung cancer.

Authors:
Mark R Green

J Clin Oncol 2008 Jul;26(19):3112-3

Network for Medical Communication and Research Analytics, Atlanta, GA, USA.

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http://dx.doi.org/10.1200/JCO.2007.15.7446DOI Listing
July 2008

Response to the methylation inhibitor dihydro-5-azacytidine in mesothelioma is not associated with methylation of p16INK4a: results of cancer and leukemia group B 159904.

J Thorac Oncol 2008 Apr;3(4):417-21

Division of Hematology-Oncology-Transplant, The University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.

Introduction: The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16INK4a. Absence of expression of the p16INK4a gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16INK4a expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16INK4a expression is known to be inactivated by hypermethylation of the first exon. This project (CALGB 159904) intended to test the hypothesis that in mesothelioma loss of p16INK4a via methylation would correlate with response to the cytidine analog and methylation inhibitor dihydro-5-azacytidine (DHAC).

Methods: Using tissue samples from CALGB 8833 and 9031, two clinical studies which used DHAC based therapy in mesothelioma, this study tested the hypothesis that tumors possessing methylation of p16INK4a would have a better response and survival following DHAC treatment than their nonmethylated counterparts.

Results: Methylation of p16INK4a was identified in 4 of the 20 specimens. Although there was a trend towards improved survival the result was not statistically significant.

Conclusions: There was no significant correlation between the presence of p16INK4a methylation and response to DHAC therapy or overall survival.
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http://dx.doi.org/10.1097/JTO.0b013e318168da0aDOI Listing
April 2008

Interruptions of once-daily thoracic radiotherapy do not correlate with outcomes in limited stage small cell lung cancer: analysis of CALGB phase III trial 9235.

Lung Cancer 2008 Oct 25;62(1):92-8. Epub 2008 Mar 25.

SUNY Upstate Medical University, Radiation Oncology Department, 750 E. Adams Street, Syracuse, NY 13210, United States.

Purpose: Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study.

Material And Methods: This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes<1000/mm3 or platelets<75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration).

Results: TRT interruptions > or =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (>70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration.

Conclusion: Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.
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http://dx.doi.org/10.1016/j.lungcan.2008.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465446PMC
October 2008

Phase II trial of weekly dose-dense paclitaxel in extensive-stage small cell lung cancer: cancer and leukemia group B study 39901.

J Thorac Oncol 2008 Feb;3(2):158-62

State University of New York Upstate Medical University, Syracuse, New York 13210, USA.

Introduction: Paclitaxel is an active agent in extensive-stage (ES) small cell lung cancer (SCLC). Nevertheless, the optimal schedule is uncertain. A dose-dense schedule was previously evaluated in a Cancer and Leukemia Group B study of patients with non-SCLC, resulting in a 42% response rate and median survival of 12.3 months. Because of these promising results, this dose and schedule of paclitaxel was evaluated in patients with ES-SCLC.

Methods: Patients were eligible for this phase II trial (Cancer and Leukemia Group B 39901) if they had documented ES-SCLC, no prior chemotherapy, and performance status of 0 to 2. Paclitaxel was administered as an intravenous infusion at 150 mg/m2 over 3 hours weekly for 6 consecutive weeks every 8 weeks.

Results: Thirty-six patients with median age of 65 were enrolled. Of them 25 were men and 33 with a performance status 0 to 1. A median of two 8-week cycles were delivered. The percent of patients with grade 3/4 toxicity included neutropenia 22%, anemia 9%, febrile neutropenia 6%, fatigue 20%, sensory neuropathy 26%, motor neuropathy 11%, and dyspnea 17%. There were two treatment-related deaths, both from pneumonitis. The overall response rate was 33% (3% complete response and 30% partial response). Median progression-free and overall survivals were 3.7 and 9.2 months, respectively. One-year progression-free and overall survivals were 17% and 36%, respectively.

Conclusions: For patients with ES-SCLC, dose-dense weekly paclitaxel was associated with fairly mild hematologic toxicity. Nevertheless, nonhematologic toxicities, including neuropathy, fatigue, and dyspnea required frequent dose delays and reductions. The overall response rate is disappointing and much lower than that seen with standard platinum-based combinations. Paclitaxel in this dose and schedule should not be used as front-line therapy for patients with ES-SCLC.
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http://dx.doi.org/10.1097/JTO.0b013e318161225eDOI Listing
February 2008

Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer.

BMC Cancer 2007 Dec 20;7:231. Epub 2007 Dec 20.

Division of Medical Oncology/Hematology, Hollings Cancer Center, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA.

Background: A platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule.

Methods: From February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days.

Results: The MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively.

Conclusion: Vinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively.

Trial Registration Number: NCT00287963.
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http://dx.doi.org/10.1186/1471-2407-7-231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2241632PMC
December 2007

Video-assisted thoracic surgery lobectomy: report of CALGB 39802--a prospective, multi-institution feasibility study.

J Clin Oncol 2007 Nov;25(31):4993-7

Surgery Committee of the Cancer and Leukemia Group B (CALGB), Statistics Office of CALGB, and Respiratory Committee of CALGB, Chicago, IL, USA.

Purpose: To evaluate the technical feasibility and safety of video-assisted thoracic surgery (VATS) lobectomy for small lung cancers.

Patients And Methods: The Cancer and Leukemia Group B 39802 trial was a prospective, multi-institutional study designed to elucidate the technical feasibility of VATS in early non-small-cell lung cancer (NSCLC) using a standard definition for VATS lobectomy (one 4- to 8-cm access and two 0.5-cm port incisions) that mandated videoscopic guidance and a traditional hilar dissection without rib spreading. Between 1998 and 2001, 128 patients with peripheral lung nodules < or = 3 cm in size with suspected NSCLC were prospectively registered for VATS lobectomy.

Results: One hundred twenty-seven patients (66 males and 61 females; median age, 66 years; range, 37 to 86 years), with a performance status of 0 (74%) or 1 (26%), underwent surgery. Patients with lymph nodes more than 1 cm by computed tomography scan underwent mediastinal lymph node sampling to rule out N2 disease. One hundred eleven patients (87%) had stage I lung cancer, and 96 (86.5%) of these 111 patients underwent successful VATS lobectomies. The median procedure length was 130 minutes (range, 47 to 428 minutes), and median chest tube duration was 3 days (range, 1 to 14 days). Fifty-eight (60%) of 97 patients underwent diagnostic biopsy at lobectomy. Within 30 days, three (2.7%) of 111 patient deaths occurred, none of which were directly related to VATS technique; seven (7.4%) of 95 patients had grade 3 or greater complications, with only one case of bleeding.

Conclusion: A standardized approach to VATS lobectomy as specifically defined with avoidance of rib spreading is feasible.
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http://dx.doi.org/10.1200/JCO.2007.12.6649DOI Listing
November 2007

Irinotecan-cisplatin therapy for patients with extensive-stage small cell lung cancer: use patterns among American medical oncologists 2000-2006.

J Thorac Oncol 2007 Oct;2(10):953-6

Analytics Group, Network for Medical Communication and Research, Atlanta, Georgia, USA.

Background: Etoposide-platinum doublet therapy has been the American standard first-line management for patients with small cell lung cancer for more than a decade. In the 1990s, Japanese investigators developed a regimen of irinotecan-cisplatin for extensive-stage patients and, in one head-to-head trial, the irinotecan therapy produced a statistically significant survival advantage compared with etoposide and cisplatin. We were interested in how American oncologists integrate clinical trial data into their current prescribing practices and studied case-based prescribing recommendations as a surrogate for current clinical practice. We evaluated Network for Medical Communications and Research data from 7 years of live physician meetings to assess changes in use patterns for irinotecan cisplatin since the initial report of the Japanese clinical trial.

Methods: Data from 38 meetings involving 2174 medical professional attendees (MD; DO; MD PhD) were reviewed. Attendees were given a case scenario and asked to select the treatment option that they felt was most appropriate for the hypothetical setting provided. At each meeting, responses were collected electronically and immediately displayed to the attendees. Aggregate response data are held in the Network for Medical Communications and Research database.

Results: During the 7-year study period, regimens including etoposide and platinum have consistently been the most frequently recommended for small cell lung cancer therapy by the meeting participants. The selection of irinotecan-cisplatin by American oncologists was initially infrequent, with a modest, transient impact of a plenary session presentation of the Japanese phase III trial data at the 2000 meeting of the American Society of Clinical Oncology. Publication of the phase III trial findings in the New England Journal of Medicine in early 2002 stimulated a marked increase in irinotecan-cisplatin prescribing with a commensurate decrease in the selection of etoposide and cisplatin therapy. Since 2002, the prescribing patterns have shown an accelerating return to the use of etoposide and platinum despite continuing study of irinotecan-platinum regimens.

Conclusions: Statistically significant advantages demonstrated in a single phase III clinical trial may have only a modest and transient impact on American oncologists' prescribing behaviors. Factors other than the phase III trial results themselves play a role in the likelihood that prescribing behavior will evolve over time. Corroborating trial data among unambiguously relevant populations will be necessary to stimulate a change in standard treatment paradigms.
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http://dx.doi.org/10.1097/JTO.0b013e318153f8dbDOI Listing
October 2007

Phase II trial of paclitaxel-topotecan-etoposide followed by consolidation chemoradiotherapy for limited-stage small cell lung cancer: CALGB 30002.

J Thorac Oncol 2007 Jul;2(7):645-51

Comprehensive Cancer Center, Wake Forest University, Winston-Salem, North Carolina, USA.

Purpose: We sought to evaluate the activity and tolerance of the rationally designed sequence of paclitaxel-topotecan-etoposide, a nonplatinum regimen, as induction therapy for limited-stage small-cell lung cancer before combined chemo- and radiotherapy.

Patients And Methods: Patients with measurable disease, performance status 0 to 2, no prior therapy, and adequate organ function were eligible. Paclitaxel (110 mg/m2, administered intravenously on day 1), topotecan (1.5 mg/m2, administered orally on days 2 to 4), and etoposide (160 mg/m2, administered orally on days 5 to 7 every 21 days), with filgrastim for two cycles, were followed by chest irradiation to 70 Gy (to postinduction tumor volume) concurrent with carboplatin (area under the curve of 5, administered intravenously on day 1) and etoposide (100 mg/m2 on days 1 to 3 every 21 days) without filgrastim for three cycles (five chemotherapy cycles total). We aimed to determine the response rates to induction and overall therapy, overall and failure-free survival, and toxicity. The primary statistical endpoint was to differentiate between complete response rates of 50 and 70% for the overall treatment program.

Results: Between June 2001 and January 2003, 65 patients were enrolled, but one never started therapy, and one was ineligible. Patient characteristics included male/female, 27/36; white/black/other/unknown, 58/3/1/1; median age 62 (range, 38-78); performance status 0/1/2, 27/33/3. Induction chemotherapy resulted in six (10%) complete responses and 35 (56%) partial responses. Overall response to chemoradiotherapy included 27 (43%; 95% confidence interval [CI] 30-56%) complete responses and 24 (38%) partial responses. Median progression-free survival is 12 months (95% CI, 9-15 months). Median overall survival is 20 months (95% CI, 16-24 months). Frequent (>20%) grade 3/4 toxicities during all therapy included neutropenia, febrile neutropenia, anemia, thrombocytopenia, fatigue, and dysphagia. One patient died of febrile neutropenia, one died of febrile neutropenia and typhlitis, and one patient who declined transfusion for anemia died of cardiac ischemia.

Conclusions: This treatment regimen has significant activity in limited-stage small-cell lung cancer but did not meet our prospectively defined criteria for further investigation in this setting. The addition of etoposide and the use of a sequenced administration schedule did not seem to improve overall activity beyond our prior experience with a topotecan-paclitaxel doublet.
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http://dx.doi.org/10.1097/JTO.0b013e318074bbf5DOI Listing
July 2007

Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B.

J Clin Oncol 2007 May 2;25(13):1698-704. Epub 2007 Apr 2.

University of Chicago, Chicago, IL, USA.

Purpose: Standard therapy for unresectable stage III non-small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival.

Patients And Methods: Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients.

Results: Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors.

Conclusion: The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.
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http://dx.doi.org/10.1200/JCO.2006.07.3569DOI Listing
May 2007

A phase III study of surgical resection and paclitaxel/carboplatin chemotherapy with or without adjuvant radiation therapy for resected stage III non-small-cell lung cancer: Cancer and Leukemia Group B 9734.

Clin Lung Cancer 2007 Jan;8(4):268-72

University of Missouri/Ellis Fischel Cancer Center, Columbia, MO 65203, USA.

Purpose: Patients with completely resected stage IIIA (N2) non-small-cell lung cancer (NSCLC) are at substantial risk for locoregional and systemic recurrence. Adjuvant chemotherapy has recently improved overall control for these patients. We added adjuvant chemotherapy to control presumed micrometastatic disease and then randomized patients to receive radiation therapy (RT) or observation to determine the benefit of local radiation consolidation.

Patients And Methods: Patient eligibility required histologically documented stage IIIA (radiographically occult N2) NSCLC that was completely resected, with no known residual disease, surgical staging per protocol requirements, Cancer and Leukemia Group B performance status of 0/1, no previous chemotherapy or RT, and minimal laboratory values. All eligible patients received 4 cycles of paclitaxel 200 mg/m2 over 3 hours with carboplatin at an area under the curve of 6 on days 1, 22, 43, and 64 beginning 4-8 weeks after surgery. Two to 4 weeks after chemotherapy, patients were randomized to receive RT as 5000 cGy in 25 fractions over 5 weeks or observation.

Results: The study closed after 2 years because of slow accrual. Forty-four patients entered the study; 2 were ineligible, and 5 were not randomized because of progression, adverse reaction, or patient withdrawal. Thirty-seven patients were the basis of this analysis. Median failure-free survival was 16.8 months on the observation arm and 33.7 months on the RT arm, with a 1-year survival rate of 72% on the observation arm and 74% on the RT arm. There were no statistical differences between the observation and RT arms for failure-free survival or overall survival.

Conclusion: In this small study, consolidation RT after complete resection and adjuvant chemotherapy in stage IIIA NSCLC did not significantly improve outcome for this high-risk population.
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http://dx.doi.org/10.3816/CLC.2007.n.005DOI Listing
January 2007

Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935.

J Surg Oncol 2006 Dec;94(7):599-606

Division of Thoracic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Background And Objectives: CALGB 8935 was a phase II protocol for mediastinoscopically staged IIIA (N2) non-small cell lung cancer. Induction cisplatin/vinblastine chemotherapy was followed by surgical resection, adjuvant cisplatin/vinblastine, and radiotherapy. We now evaluate the prognosis of pathologic nodes.

Methods: Failure-free survival was calculated from a landmark 3 months after resection to account for heterogeneity in adjuvant therapy.

Results: Nine of 42 (21%) resected patients had no residual N2 disease. This subset of 9 had a median failure-free interval of 47.8 months from landmark, whereas the 33 patients (79%) with persistent N2 disease had a median failure-free survival of 8.2 months from landmark (P=0.01). Although 21/42 (50%) had an incomplete resection (positive highest resected node and/or margin), completeness of resection did not influence failure-free survival. There were 3 distant and no local recurrences among the N2 negative group, and 12 local recurrences among patients with residual N2 disease (P=0.041).

Conclusions: These data suggest: (1) persistent N2 disease following induction chemotherapy is unfavorable; (2) patients downstaged to N2 negative may benefit from surgical resection; however, (3) 33% of N2 negative patients suffered disease relapse.
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http://dx.doi.org/10.1002/jso.20644DOI Listing
December 2006

The cancer and leukemia group B respiratory committee.

Clin Cancer Res 2006 Jun;12(11 Pt 2):3581s-8s

The University of Chicago, Chicago, Illinois, USA.

The Cancer and Leukemia Group B Respiratory Committee has a 30-year track record of clinical investigation in patients with small-cell lung cancer and non-small-cell lung cancer (NSCLC) and mesothelioma. The most widely recognized contributions of the Committee include the early confirmation of the role of concurrent chemoradiotherapy in LD-SCLC, the effect of combination chemotherapy followed by radiation in stage III NSCLC, the introduction of third-generation agents into concurrent chemoradiation for stage III disease, the prospective demonstration of the benefit of treating older (70 years old) and poorer performance status (performance status = 2) patients with first-line combinations for stage IV disease, and the development of the "Herndon prognostic index" to normalize patient characteristics and outcomes in sequential phase II trials of new agents in patients with mesothelioma. Many other contributions have also emerged from the Committee's clinical trials and correlative science programs. We look forward to making additional critical contributions during future decades of Cancer and Leukemia Group B Respiratory Committee research.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-9015DOI Listing
June 2006